The New York Center for Systems Biology (NYCSB) brings together researchers and educators from Mount Sinai SOM, Columbia Univ College of Physicians, Courant Inst of Mathematical Sciences NYU, SUNY Stony brook, City College CUNY and the IBM T.J Watson Research Lab to integrate theoretical and experimental approaches for a deep mechanistic understanding of multi-scale functional organization of mammalian physiological/pathophysiological systems and how drugs (therapeutic and abusive) affect this organization. We want to understand how the effects of molecular interactions are propagated across scales of organization from cells to tissues and organs affecting physiology and pathophysiology. We posit that the dynamic organization of motifs (regulatory loops) within multi-scale networks provides the basis for propagation of effects across scales from molecules to cells to tissues. Drugs have their effects by reorganizing network topology across these scales. We study selected processes in the heart and brain to test these hypotheses. We are developing and seamlessly integrating multiple modeling approaches including graph theory analysis, differential equation-based modeling and the new method of stochastic reaction-diffusion to model processes in 3D. Such thoeretical integration allows us to construct and analyze multi-scale models. We are developing parallelized programs that run on supercomputers such as IBM Blue-Gene/L both for dynamic motif searches in large networks and for simulations of differential equationbased models. The theoretical studies are well integrated with multivariable experiments to profile activity changes by reverse protein arrays, transcription factor arrays and microarrays. The multivariable experiments in turn are combined with quantitative measurements of molecular interactions and tissue level physiological measurements to constrain models and test model predictions. The research activities of the NYCSB form a continum with our educational and outreach activities that include graduate and postdoctoral training, summer programs for undergraduates with a focus on recruiting underepresented minorities, training undergraduate educators, personalized workshops and opportunities to partcipate in the NYCSB research projects for all researchers. Together these research, education and outreach activities will allow NYSBC make significant contributions towards the development of Systems Medicine and Therapeutics.